Mouse models of respiratory inflammation have been indispensable to the dissection of immune pathways that result in lung remodeling and dysfunction. The value of these models results not only from their ability to represent the inflammation occurring in human disease but also from their usefulness in reductionist approaches examining specific cells and/or inflammatory pathways. Previous attempts using mice to examine the role of eosinophils in respiratory inflammation have been limited by the nominal character of disease pathology occurring in these models (i.e., the observed pathologies are only a subset of those occurring in humans) as well as differences observed between eosinophil activities occurring in the lungs of asthma patients and those in the established mouse models (i.e., eosinophils in these models displayed little evidence of granule protein release (i.e., degranulation)). These limitations have led us to create an allergen- naive double transgenic mouse (I5/hE2) that expresses IL-5 systemically from mature T cells and eotaxin-2 locally from lung epithelial cells. I5/hE2 mice develop many pulmonary pathologies that were absent in earlier mouse models but which nonetheless occur in severe asthma patients. More importantly, extensive eosinophil degranulation in the lung (previously only associated with asthma patients) accompanies the pathologies in the I5/hE2 model. In addition, we have demonstrated that all of the pathologies in I5/hE2 mice are absolutely dependent on the induced pulmonary eosinophilia. This proposal capitalizes on the availability of the I5/hE2 transgenic model as well as our unique eosinophil-less line of mice (PHIL) to test the central hypothesis that eosinophils themselves are the relevant source of the molecules commonly suggested to be responsible for remodeling and airway dysfunction. The objectives of the proposal will be achieved using these mice and other novel eosinophil-specific reagents/methodologies by the completion of the following Specific Aims: (1) To determine if immunoregulation of the pulmonary microenvironment by eosinophils contributes to inflammatory responses leading to pulmonary pathologies; (2) To demonstrate that eosinophil- derived TGF-1 activities directly contribute to pulmonary remodeling events and lung dysfunction; (3) To define the pulmonary remodeling events, including induced lung dysfunction, mediated by the release of eosinophil granule proteins. PUBLIC HEALTH RELEVANCE: The scientific literature abounds with studies which question whether the recruitment to the lung of a unique white blood cell, the eosinophil, contributes to the development of asthma. Clearly, these conflicting reports suggest that the importance of eosinophils is not fully understood. Our development of a novel mouse asthma model replicating the hallmark features of this disease provides a unique ability to understand the roles of eosinophils in lung inflammation and an invaluable resource for the development of therapeutic strategies.